Abstract
For many years, a connection between circadian clocks and cancer has been postulated. Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, although the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation. Their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.
Original language | English |
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Pages (from-to) | 774-789 |
Number of pages | 16 |
Journal | Molecular Cell |
Volume | 64 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2016 Nov 17 |
Subject classification (UKÄ)
- Cell and Molecular Biology
Free keywords
- circadian clock
- circadian rhythm
- CRY2
- cryptochrome
- FBXL3
- MYC
- ubiquitin